International Journal of Molecular Sciences Review Beneficial Impacts of Alpha-Eleostearic Acid from Wild Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur Domain 2: Therapeutic Roles in CNS Injuries and Diseases Woon-Man Kung 1 and Muh-Shi Lin 2,3,4,5,* 1 Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei 11114, Taiwan; [email protected] 2 Division of Neurosurgery, Department of Surgery, Kuang Tien General Hospital, Taichung 43303, Taiwan 3 Department of Biotechnology and Animal Science, College of Bioresources, National Ilan University, Yilan 26047, Taiwan 4 Department of Biotechnology, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan 5 Department of Health Business Administration, College of Medical and Health Care, Hung Kuang University, Taichung 43302, Taiwan * Correspondence: [email protected]; Tel.: +886-4-2665-1900 Abstract: Neuroinflammation and abnormal mitochondrial function are related to the cause of aging, neurodegeneration, and neurotrauma. The activation of nuclear factor κB (NF-κB), exaggerating these two pathologies, underlies the pathogenesis for the aforementioned injuries and diseases in the central nervous system (CNS). CDGSH iron-sulfur domain 2 (CISD2) belongs to the human NEET protein family with the [2Fe-2S] cluster. CISD2 has been verified as an NFκB antagonist through the Citation: Kung, W.-M.; Lin, M.-S. association with peroxisome proliferator-activated receptor-β (PPAR-β). This protective protein can Beneficial Impacts of be attenuated under circumstances of CNS injuries and diseases, thereby causing NFκB activation Alpha-Eleostearic Acid from Wild and exaggerating NFκB-provoked neuroinflammation and abnormal mitochondrial function. Conse- Bitter Melon and Curcumin on Promotion of CDGSH Iron-Sulfur quently, CISD2-elevating plans of action provide pathways in the management of various disease Domain 2: Therapeutic Roles in CNS categories. Various bioactive molecules derived from plants exert protective anti-oxidative and anti- Injuries and Diseases. Int. J. Mol. Sci. inflammatory effects and serve as natural antioxidants, such as conjugated fatty acids and phenolic 2021, 22, 3289. https://doi.org/ compounds. Herein, we have summarized pharmacological characters of the two phytochemicals, 10.3390/ijms22073289 namely, alpha-eleostearic acid (α-ESA), an isomer of conjugated linolenic acids derived from wild bitter melon (Momordica charantia L. var. abbreviata Ser.), and curcumin, a polyphenol derived from Academic Editor: Luigi Brunetti rhizomes of Curcuma longa L. In this review, the unique function of the CISD2-elevating effect of α-ESA and curcumin are particularly emphasized, and these natural compounds are expected to Received: 6 March 2021 serve as a potential therapeutic target for CNS injuries and diseases. Accepted: 21 March 2021 Published: 24 March 2021 Keywords: alpha-eleostearic acid; curcumin; aging; neurodegenerative disease; neurotrauma; CISD2; neuroinflammation; mitochondrial dysfunction; NFκB Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Preface Neuroinflammation is critically involved in the pathophysiology of acute injuries and diseases (including aging and neurodegeneration) in the central nervous system (CNS) [1–4]. Profound inflammatory responses are characterized by the activation of glial Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. cells, which are primary innate immune cells of the CNS. Neuroinflammation can induce This article is an open access article mitochondrial dysfunction. The main feature is that these reactive glial cells produce distributed under the terms and nitric oxide (NO) as well as reactive oxygen species (ROS) [5]. Both mutually influencing conditions of the Creative Commons pathogeneses, inflammation, mitochondrial dysfunction, and eventually neuronal function Attribution (CC BY) license (https:// of the CNS [6,7]. creativecommons.org/licenses/by/ Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has been shown 4.0/). to involve in inflammation and mitochondrial dysfunction [8,9]. NFκB activation can be Int. J. Mol. Sci. 2021, 22, 3289. https://doi.org/10.3390/ijms22073289 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 19 Int. J. Mol. Sci. 2021, 22, 3289 2 of 19 neuronal function of the CNS [6,7]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) has been shown to involve in inflammation and mitochondrial dysfunction [8,9]. NFκB activation inhibitedcan be inhibited by a distinctive by a distinctive zinc finger zinc finger in addition in addition to the to iron-sulfur the iron-sulfur protein, protein CDGSH, CDGSH iron- sulfuriron-sulfur domain domain 2 (CISD2) 2 (CISD2 [10]. The) [10] preventive. The preventive effect of CISD2effect of in oppositionCISD2 in opposition to inflammation, to in- andflammation abnormal, and mitochondrial abnormal mitochondrial function supports function its supports role to act itsas role a therapeuticto act as a therapeutic target for CNStarge injuriest for CNS and injuries diseases. and diseases. CISD2 expressionexpression levellevel isis decreaseddecreased duringduring CNSCNS injuriesinjuries andand diseasesdiseases [[1010––1313].]. AsAs aa controllercontroller ofof NFNFκκBB activation, activation, CISD2 CISD2 attenuation attenuation leads leads to to an an exaggerated exaggerated NF κNFB activation.κB activa- Thistion. reviewThis review has focused has focused on the on neuromodulatory the neuromodulatory effects effects of phytochemicals, of phytochemicals such as, such alpha- as eleostearicalpha-eleostearic acid (α acid-ESA) (α- fromESA)Momordica from Momordica charantia charantiaL. var. L. abbreviata var. abbreviata Ser. (Cucurbitaceae) Ser. (Cucurbi- (commonlytaceae) (commonly named asnamed wild bitteras wild melon, bitter WBM)melon, [ 10WBM)], and [10], curcumin and curcumin from Curcuma from Curcuma longa L. (Zingiberaceae)longa L. (Zingiberaceae) [12,13], along [12,13], with a thelong emphasis with the of emphasi CISD2-elevatings of CISD2 effects-elevating of these effects natural of compounds.these natural Natural compounds medicine. Natural beneficial medicine to CNS beneficial pathology-NF to CNSκ pathologyB-CISD2 axis-NFκB (Figure-CISD21) canaxisbe (Figure recommended 1) can be torecommended treat CNS injuries to treat and CNS diseases. injuries and diseases. FigureFigure 1. DiagramDiagram of of CNS CNS pathology pathology–CISD2-NF–CISD2-NFκBκ Baxis. axis. CDGSH CDGSH iron iron-sulfur-sulfur domain domain 2 (CISD2 2 (CISD2)) expression can be reduced under circumstances of CNS injuries and diseases, such as aging, neu- expression can be reduced under circumstances of CNS injuries and diseases, such as aging, neurode- rodegenerative disease, and neurotrauma. CISD2 serves as NFκB antagonist. As such, inju- generative disease, and neurotrauma. CISD2 serves as NFκB antagonist. As such, injury-induced ry-induced decline in CISD2 leads to enhanced NFκB and thereby NFκB-provokes neuroinflam- κ κ declinemation inand CISD2 mitochondrial leads to enhanced dysfunction. NF B CISD2 and thereby-elevating NF strategiesB-provokes help neuroinflammation to mitigate and mito- chondrialNFκB-provoked dysfunction. inflammation CISD2-elevating and mitochondrial strategies help dysfunction to mitigate. Curcumin NFκB-provoked from Curcuma inflammation longa L. and mitochondrialand α-ESA from dysfunction. Momordica Curcumincharantia L. from var. Curcumaabbreviata longa Ser. L.(w andild bitterα-ESA melon) from Momordicaexert an- charantia L. var.ti-inflammatory abbreviata Ser. and(wild CISD2 bitter-preservation melon) exert effect anti-inflammatorys. Any novel plant and e CISD2-preservationxtracts able to exhibit effects. neuro- Any novelmodulat plantory extractseffects on able this to axis exhibit of CNS neuromodulatory pathology–CISD2 effects-NFκB on thiscan axisbe co ofnsidered CNS pathology–CISD2- to be applied in NFCNSκB injuries can be consideredand diseases. to be applied in CNS injuries and diseases. 2.2. InnateInnate Immune Cells in the CNS—MicrogliaCNS—Microglia andand AstrocytesAstrocytes InIn general,general, microgliamicroglia andand astrocytesastrocytes areare residentresident glialglial cellscells inin thethe CNS,CNS, andand thesethese twotwo groupsgroups ofof cellscells cancan bebe activatedactivated inin responseresponse toto CNSCNS injuriesinjuries andand diseases,diseases, consequentlyconsequently causingcausing locallocal inflammatoryinflammatory response,response, i.e.,i.e., neuroinflammationneuroinflammation [[14].14]. AsAs withwith peripheralperipheral macrophages,macrophages, microgliamicroglia areare embryologicallyembryologically derivedderived fromfrom myeloidmyeloid progenitors,progenitors, whereaswhereas astrocytesastrocytes areare derivedderived fromfrom neuroepithelialneuroepithelial precursorsprecursors [[15].15]. To maintainmaintain CNSCNS homeostasis, homeostasis microglia, microglia and and astrocytes astrocytes provide provide support support and and supply sup- nutritionply nutrition for neurons.for neurons Microglia. Microglia provide provide neurotrophic neurotrophic support support for neurons for neurons and mainly and mediatemainly mediate immune immune responses responses to stabilize to stabilize the CNS the [16 CNS]. Astrocyte-mediated [16]. Astrocyte-mediated neuroprotec- neuro- tion has been proposed to